SYNJARDY XR
Clinical safety rating: caution
Comprehensive clinical and safety monograph for SYNJARDY XR (SYNJARDY XR).
Synjardy XR is a combination of empagliflozin, an SGLT2 inhibitor that reduces renal glucose reabsorption, and metformin, an AMPK activator that decreases hepatic glucose production and improves insulin sensitivity.
| Metabolism | Metformin is excreted unchanged in urine; no significant metabolism. Empagliflozin is primarily metabolized via glucuronidation by UGT2B7, UGT1A3, UGT1A8, and UGT1A9; minimal CYP450 involvement. |
| Excretion | Empagliflozin: Approximately 54% excreted unchanged in urine, 41% in feces (metabolites). Metformin: ~90% excreted unchanged in urine via tubular secretion and glomerular filtration; renal clearance ~510 mL/min. |
| Half-life | Empagliflozin: Terminal half-life ~12.4 hours (supports once-daily dosing). Metformin: Terminal half-life ~6.2 hours (plasma); elimination half-life prolonged in renal impairment (up to 17.6 hours in patients with reduced GFR). |
| Protein binding | Empagliflozin: ~86% bound to plasma proteins. Metformin: Negligible protein binding (<5%). |
| Volume of Distribution | Empagliflozin: Apparent Vd ~1.8 L/kg (extensive tissue distribution). Metformin: Apparent Vd ~654 L (absolute) or 9.3 L/kg (large distribution into tissues, particularly gastrointestinal tract and liver). |
| Bioavailability | Empagliflozin: Absolute bioavailability ~78% (oral). Metformin: Extended-release tablet bioavailability ~50-60% compared to immediate-release (with food possibly increasing absorption). |
| Onset of Action | Empagliflozin: Onset of urinary glucose excretion within 24 hours; maximal effect by 1-2 weeks. Metformin: Onset of glucose-lowering effect within 2-3 days; full effect in 1-2 weeks. |
| Duration of Action | Empagliflozin: Duration of pharmacodynamic effect (increased urinary glucose excretion) supports 24-hour dosing interval. Metformin: Duration of action ~8-12 hours; extended-release formulation provides sustained effect over 24 hours. |
Initial dose: 5 mg empagliflozin/500 mg metformin extended-release orally twice daily with meals. Titrate based on glycemic control and tolerability up to maximum 25 mg empagliflozin/1000 mg metformin XR twice daily.
| Dosage form | TABLET, EXTENDED RELEASE |
| Renal impairment | eGFR ≥60 mL/min/1.73m²: no adjustment. eGFR 45-59: maximum dose 12.5 mg empagliflozin/1000 mg metformin XR twice daily; contraindicated if eGFR <45 (initiation) or <30 (contraindicated). Discontinue if eGFR persistently <45. |
| Liver impairment | Contraindicated in Child-Pugh Class B or C. Use with caution in Class A; maximum metformin dose 1000 mg/day. |
| Pediatric use | Safety and efficacy not established in pediatric patients under 18 years; no dosing recommendations available. |
| Geriatric use | Age ≥65: start with lowest dose (5/500 mg twice daily) and titrate cautiously due to risk of volume depletion, hypotension, and renal impairment. Assess renal function before initiation and regularly. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for SYNJARDY XR (SYNJARDY XR).
| Breastfeeding | Metformin is excreted into breast milk in low amounts with M/P ratio 0.35-0.71; empagliflozin is excreted in animal milk, unknown in humans. Insufficient data on safety; use not recommended. |
| Teratogenic Risk | First trimester: Limited data; empagliflozin shows no increased risk in animal studies; metformin not associated with malformations. Second and third trimesters: Potential risk of fetal hypoglycemia and altered fetal growth from metformin; empagliflozin may affect fetal renal development and should be avoided. |
■ FDA Black Box Warning
Lactic acidosis: Metformin-associated lactic acidosis is a rare but serious complication. Risk factors include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors), age 65 or older, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Discontinue Synjardy XR if lactic acidosis is suspected.
| Serious Effects |
["Severe renal impairment (eGFR < 30 mL/min/1.73 m²)","End-stage renal disease or dialysis","Acute or chronic metabolic acidosis, including diabetic ketoacidosis (with or without coma)","History of hypersensitivity reaction to empagliflozin, metformin, or any components","Patients with type 1 diabetes mellitus (not indicated)"]
| Precautions | ["Lactic acidosis (see black box warning)","Ketoacidosis: Assess for ketoacidosis in patients with signs/symptoms, even if blood glucose is near normal; discontinue if suspected","Hypotension: May cause intravascular volume contraction, especially in patients with renal impairment, elderly, or those on diuretics","Acute kidney injury: Monitor renal function; more common in patients with volume depletion or on NSAIDs","Urosepsis and pyelonephritis: Evaluate for urinary tract infections; discontinue if complicated UTI develops","Hypoglycemia: When used with insulin or sulfonylureas, lower doses may be required","Genital mycotic infections: Increased risk, especially in patients with history","Necrotizing fasciitis of the perineum (Fournier's gangrene): Discontinue if symptoms develop","Vitamin B12 deficiency: May decrease B12 levels; monitor periodically","Increased LDL-C: Monitor lipid profile"] |
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| Fetal Monitoring |
| Monitor maternal renal function, glucose levels, and fetal growth via ultrasound; assess for neonatal hypoglycemia and renal effects after delivery. |
| Fertility Effects | Empagliflozin and metformin are not associated with adverse effects on female or male fertility based on animal studies; no human data available. |